Optimized sensor geometry for an implantable glucose sensor

ABSTRACT

An implantable sensor for use in measuring a concentration of an analyte such as glucose in a bodily fluid, including a body with a sensing region adapted for transport of analytes between the sensor and the bodily fluid, wherein the sensing region is located on a curved portion of the body such that when a foreign body capsule forms around the sensor, a contractile force is exerted by the foreign body capsule toward the sensing region. The body is partially or entirely curved, partially or entirely covered with an anchoring material for supporting tissue ingrowth, and designed for subcutaneous tissue implantation. The geometric design, including curvature, shape, and other factors minimize chronic inflammatory response at the sensing region and contribute to improved performance of the sensor in vivo.

This application is a division of U.S. application Ser. No. 10/646,333filed Aug. 22, 2003, which claims the benefit of priority under 35U.S.C. §119(e) to U.S. Provisional Application No. 60/460,825, filedApr. 4, 2003, the contents of which are hereby incorporated by referencein their entirety.

FIELD OF THE INVENTION

The present invention relates generally to implantable sensors thatmeasure the concentration of an analyte in a biological fluid. Thesensor geometry optimizes the healing at the sensor-tissue interface andis less amenable to accidental movement due to shear and rotationalforces than other sensor configurations.

BACKGROUND OF THE INVENTION

Implantable analyte sensors that are placed in the subcutaneous tissueor other soft tissue sites must develop and sustain a stablebiointerface that allows the continuous and timely transport of analytesacross the interface between the tissue and the device. For example, inthe case of a glucose sensor, glucose must be able to freely diffusefrom surrounding blood vessels to a membrane of the sensor. Glucosesensors may be implanted in the subcutaneous tissue or other softtissue. Such devices include glucose oxidase based amperometric sensorsthat sense glucose for weeks, months or longer after implantation.

While the utility of such devices for glucose sensing has beendemonstrated, the consistency of function for such devices is notoptimal. For a particular device, the sensor may, for example: 1) failto function (namely, fail to track glucose effectively) in a stablemanner during the first few weeks after implantation; 2) not work at allduring the first few weeks, but subsequently begin to function in astable manner; 3) function well during the first few weeks, losefunction, then regain effectiveness or never recover function; or 4)work immediately, and continue to function with high accuracy throughoutthe course of a several month study.

Glucose sensors with improved acceptance within the host tissue anddecreased variability of response are required for reliablefunctionality in vivo. Accordingly, the present invention disclosessystems and methods for providing this improved functionality andconsistency of analyte sensor in a host.

SUMMARY OF THE INVENTION

A sensor, especially a sensor suitable for implantation into soft tissuethat provides accurate analyte measurements while offering consistencyof function is highly desirable.

Accordingly, in a first embodiment an implantable sensor is provided foruse in measuring a concentration of an analyte in a bodily fluid, thesensor including a body including a sensing region adapted for transportof analytes between the sensor and the bodily fluid, wherein the sensingregion is located on a curved portion of the body such that when aforeign body capsule forms around the sensor, a contractile force isexerted by the foreign body capsule toward the sensing region.

In an aspect of the first embodiment, the sensor is a subcutaneoussensor.

In an aspect of the first embodiment, the sensor is an intramuscularsensor.

In an aspect of the first embodiment, the sensor is an intraperitonealsensor.

In an aspect of the first embodiment, the sensor is an intrafascialsensor.

In an aspect of the first embodiment, the sensor is suitable forimplantation in an axillary region.

In an aspect of the first embodiment, the sensor is suitable forimplantation in a soft tissue of a body.

In an aspect of the first embodiment, the sensor is suitable forimplantation at the interface between two tissue types.

In an aspect of the first embodiment, the sensor includes a plurality ofsensor regions.

In an aspect of the first embodiment, the plurality of sensor regionsare located on curved portions of the body.

In an aspect of the first embodiment, the body includes a first majorsurface and a second major surface, and wherein the sensing region islocated on the first surface, and wherein the second surface is flat.

In an aspect of the first embodiment, the body includes a first majorsurface and a second major surface, and wherein the sensing region islocated on the first major surface, and wherein the second major surfaceincludes a curvature.

In an aspect of the first embodiment, the body includes a first majorsurface and a second major surface, and wherein the sensor region issituated at a position on the first major surface offset from a centerpoint of the first major surface.

In an aspect of the first embodiment, the body includes a first majorsurface and a second major surface, and wherein the sensor region issituated on the first major surface approximately at a center point ofthe first major surface.

In an aspect of the first embodiment, the body includes a first surfaceand a second surface, and wherein the sensor region is situatedapproximately at an apex of the first surface.

In an aspect of the first embodiment, the body includes a first surfaceand a second surface, and wherein the first surface, when viewed from adirection perpendicular to a center of the first surface, has asubstantially rectangular profile.

In an aspect of the first embodiment, the body includes a first surfaceand a second surface, and wherein the first surface, when viewed from adirection perpendicular to a center of the first surface, has asubstantially rectangular profile with rounded corners.

In an aspect of the first embodiment, the body includes a first surfaceand a second surface, and wherein the first surface, when viewed from adirection perpendicular to a center of the first surface, has asubstantially oval profile.

In an aspect of the first embodiment, the body includes a first surfaceand a second surface, and wherein the first surface, when viewed from adirection perpendicular to a center of the first surface, has asubstantially circular profile.

In an aspect of the first embodiment, the body is substantially cuboidaldefined by six faces, eight vertices, and twelve edges, wherein at leastone of the faces includes the sensing region.

In an aspect of the first embodiment, at least two of the faces aresubstantially curved.

In an aspect of the first embodiment, at least four of the faces aresubstantially curved.

In an aspect of the first embodiment, all six of the faces aresubstantially curved.

In an aspect of the first embodiment, the edges are substantiallyrounded.

In an aspect of the first embodiment, the vertices are substantiallyrounded.

In an aspect of the first embodiment, the entire body is curved.

In an aspect of the first embodiment, the body is substantiallycylindrical defined by a curved lateral surface and two ends, andwherein the sensor region is located on the lateral surface.

In an aspect of the first embodiment, the body is substantiallycylindrical defined by a curved lateral surface and two ends, andwherein at least one of the ends includes the substantially curvedportion on which the sensor region is located.

In an aspect of the first embodiment, the body is substantiallyspherical.

In an aspect of the first embodiment, the body is substantiallyellipsoidal.

In an aspect of the first embodiment, the body includes a first surfaceon which the sensing region is located and a second surface, and whereinthe first surface includes anchoring material thereon for supportingtissue ingrowth.

In an aspect of the first embodiment, the second surface is locatedopposite the first surface, and wherein the second surface includesanchoring material thereon for supporting tissue ingrowth.

In an aspect of the first embodiment, the second surface is locatedopposite the first surface, and wherein the second surface issubstantially smooth and includes a biocompatible material that isnon-adhesive to tissues.

In an aspect of the first embodiment, the second surface is curved.

In an aspect of the first embodiment, a mechanical anchoring mechanismis formed on the body.

In an aspect of the first embodiment, the curved portion includes aplurality of radii of curvature.

In an aspect of the first embodiment, the curved portion includes aradius of curvature between about 0.5 mm and about 10 cm.

In an aspect of the first embodiment, the curved portion includes aradius of curvature between about 1 cm and about 5 cm.

In an aspect of the first embodiment, the curved portion includes aradius of curvature between about 2 cm and about 3 cm.

In an aspect of the first embodiment, the curved portion includes aradius of curvature between about 2.5 cm and about 2.8 cm.

In an aspect of the first embodiment, the sensor includes a majorsurface and wherein the curved portion is located on at least a portionof the major surface.

In an aspect of the first embodiment, the body further includes a flatportion adjacent the curved portion.

In an aspect of the first embodiment, an interface between the flatportion and the curved portion includes a gradual transition.

In an aspect of the first embodiment, the body includes a first majorsurface on which the sensing region is located and a second majorsurface, and wherein the first and second major surfaces togetheraccount for at least about 40% of the surface area of the device.

In an aspect of the first embodiment, the first and second majorsurfaces together account for at least about 50% of the surface area ofthe device.

In an aspect of the first embodiment, the body includes a first majorsurface on which the sensing region is located and a second majorsurface, wherein the first major surface has edges between which a widthof the first major surface can be measured, and wherein the sensingregion is spaced away from the edges by a distance that is at leastabout 10% of the width of the first major surface.

In an aspect of the first embodiment, the sensing region is spaced awayfrom the edges by a distance that is at least about 15% of the width ofthe first major surface.

In an aspect of the first embodiment, the sensing region is spaced awayfrom the edges by a distance that is at least about 20% of the width ofthe first major surface.

In an aspect of the first embodiment, the sensing region is spaced awayfrom the edges by a distance that is at least about 25% of the width ofthe first major surface.

In an aspect of the first embodiment, the sensing region is spaced awayfrom the edges by a distance that is at least about 30% of the width ofthe first major surface.

In an aspect of the first embodiment, the spacing of the sensing regionfrom the edges is true for at least two width measurements, whichmeasurements are taken generally transverse to each other.

In an aspect of the first embodiment, the body includes a first majorsurface on which the sensing region is located and a second majorsurface, wherein the first major surface is at least slightly convex.

In an aspect of the first embodiment, a reference plane may be definedthat touches the first major surface at a point spaced in from edges ofthe first major surface, and is generally parallel to the first majorsurface, and is spaced away from opposite edges of the first majorsurface due to convexity of the first major surface, and wherein alocation of an edge is the point at which a congruent line or a normalline is angled 45 degrees with respect to the reference plane.

In an aspect of the first embodiment, the reference plane is spaced fromthe edges a distance that is at least about 3% from the edges, and notmore than 50% of the width.

In an aspect of the first embodiment, the reference plane is spaced fromthe edges a distance that is at least about 3% from the edges, and notmore than 25% of the width.

In an aspect of the first embodiment, the reference plane is spaced fromthe edges a distance that is at least about 3% from the edges, and notmore than 15% of the width.

In an aspect of the first embodiment, the body includes a first majorsurface on which the sensing region is located, and wherein edges of thefirst major surface are rounded and transition smoothly away from thefirst major surface.

In an aspect of the first embodiment, the body defines a surface area,and wherein between 10 % and 100% of the surface area is convexlycurved.

In an aspect of the first embodiment, the body defines a surface area,and wherein a substantial portion of the surface area is convexlycurved.

In an aspect of the first embodiment, the body defines a surface area,and where at least about 90 % of the surface area is convexly curved.

In an aspect of the first embodiment, the body includes plastic.

In an aspect of the first embodiment, the plastic is selected from thegroup consisting of thermoplastic and thermoset.

In an aspect of the first embodiment, the thermoset is epoxy.

In an aspect of the first embodiment, the thermoset is silicone.

In an aspect of the first embodiment, the thermoset is polyurethane.

In an aspect of the first embodiment, the plastic is selected from thegroup consisting of metal, ceramic, and glass.

In an aspect of the first embodiment, a porous biointerface materialthat covers at least a portion of the sensing region.

In an aspect of the first embodiment, the biointerface material includesinterconnected cavities dimensioned and arranged to create contractileforces that counteract with the generally uniform downward fibroustissue contracture caused by the foreign body capsule in vivo andthereby interfere with formation of occlusive cells.

In an aspect of the first embodiment, the sensor is a glucose sensor.

In a second embodiment, an implantable sensor is provided for use inmeasuring a concentration of an analyte in a bodily fluid, the sensorincluding: a body including a sensing region on a major surface of thebody, wherein the major surface includes a continuous curvaturesubstantially across the entire surface such that when a foreign bodycapsule forms around the sensor, a contractile force is exerted by theforeign body capsule toward the sensing region.

In a third embodiment, a wholly implantable sensor is provided tomeasure a concentration of an analyte in a bodily fluid, including: awholly implantable body including a sensing region adapted for transportof analytes between the sensor and the bodily fluid, wherein the sensingregion is located on a curved portion of a first surface of the body andwherein the first surface includes anchoring material thereon forsupporting tissue ingrowth.

In a fourth embodiment, an implantable sensor is provided to measure aconcentration of an analyte in a bodily fluid, including: a body havinga first major surface and, opposite thereto, a second major surface,wherein the first major surface is generally planar, slightly convex,and has rounded edges, with a sensor region located on the first majorsurface that is spaced away from the rounded edges, wherein the firstmajor surface is sufficiently convex that when a foreign body capsuleforms around the sensor, contractile forces are exerted therebygenerally uniformly towards the sensing region.

In a fifth embodiment, an implantable sensor is provided for use inmeasuring a concentration of an analyte in a bodily fluid, the sensorincluding: a body, the body including a sensing region adapted fortransport of analytes between the sensor and the bodily fluid, whereinthe sensing region is located on a curved portion of the body, andwherein a thermoset material substantially encapsulates the body outsidethe sensing region.

In a sixth embodiment, an implantable sensor for use in measuring aconcentration of an analyte in a bodily fluid, the sensor including:sensing means for measuring a concentration of analyte in a bodilyfluid; and housing means for supporting the sensing means, wherein thesensing means is located on a curved portion of housing means such thatwhen a foreign body capsule forms around the housing means, acontractile force is exerted by the foreign body capsule toward thesensing means.

In a seventh embodiment, an implantable drug delivery device is providedthat allows transport of analytes between the device and a bodily fluid,the device including: a body including an analyte transport regionadapted for transport of analytes between the device and the bodilyfluid, wherein the transport region is located on a curved portion ofthe body such that when a foreign body capsule forms around the device,a contractile force is exerted by the foreign body capsule toward theanalyte transport region.

In an eighth embodiment, an implantable cell transplantation device isprovided that allows transport of analytes between the device and abodily fluid, the device including: a body including an analytetransport region adapted for transport of analytes between the deviceand the bodily fluid, wherein the transport region is located on acurved portion of the body such that when a foreign body capsule formsaround the device, a contractile force is exerted by the foreign bodycapsule toward the analyte transport region.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of classical foreign body response to anobject implanted under the skin.

FIG. 2A is schematic side view of a prior art device that has a sensingregion with an abrupt inside turn, causing a sub-optimal foreign bodyresponse.

FIG. 2B is a photomicrograph of the foreign body response to a portionof the device of FIG. 2A, after formation of the foreign body capsuleand subsequent explantation, showing thickened immune response adjacentto the abrupt inside turn.

FIG. 3A is a schematic side view of another prior art device that hasflattened surfaces across the entire device, and particularly across thesensing region, causing sub-optimal foreign body capsule healing.

FIG. 3B is a schematic side view of the sensing region of yet anotherdevice that has flattened surfaces across the entire device, and aninset sensing region, which is an example of another device that causessub-optimal foreign body capsule healing in implantable sensors.

FIG. 4 is a cross-sectional view of the sensing region of an analytesensor in one embodiment of the present invention, wherein the sensingregion is continuously curved, thereby causing contractile forces fromthe foreign body capsule to press downwardly on the sensing region.

FIG. 5A is a perspective view of an analyte sensor in anotherembodiment, including a thin oblong body, a curved sensing region, andan overall curved surface on which the sensing region is located,thereby causing contractile forces from the foreign body capsule topress downward on the sensor head.

FIG. 5B is the analyte sensor of FIG. 5A shown implanted with thesensing region adjacent to the fascia underlying the subcutaneous space,and overlaying adjacent muscle.

FIG. 5C is an end view of the analyte sensor of FIG. 5A showing thecontractile forces caused by the foreign body capsule.

FIG. 5D is a side view of the analyte sensor of FIG. 5A.

FIG. 6 is a perspective view of sensor geometry in an alternativeenvironment wherein the sensor includes a curved sensor region and aflat region, wherein the interface between the flat region and thecurved region includes a gradual transition.

FIG. 7 is a perspective view of sensor geometry in an alternativeembodiment wherein the entire sensor body is curved.

FIG. 8 is a perspective view of sensor geometry in an alternativeembodiment including a cylindrical geometry wherein a plurality ofsensing regions are located on the curved lateral surface of the sensorbody.

FIG. 9A is a perspective view of sensor geometry in an alternativeembodiment including a substantially spherical body wherein a pluralityof sensing regions are located about the circumference of the sphere.

FIG. 9B is a perspective view of a sensor geometry in an alternativeembodiment including a substantially spherical body with a rod extendingtherefrom.

FIGS. 10A to 10D are perspective views of a sensor that has anexpandable sensing body in one embodiment. FIGS. 10A and 10C are viewsof the sensor with the sensing body in a collapsed state, FIGS. 10B and10D are views of the sensor with the sensing body in an expanded state.

FIGS. 11A to 11D are perspective views of sensors wherein one or moresensing bodies are tethered to an electronics body in a variety ofalternative embodiments.

FIGS. 12A to 12B are perspective views of a sensor in an alternativeembodiment wherein an electronics body is independent of the sensingbodies in a preassembled state and wherein the sensing bodies areindependently inserted (and operatively connected) to the electronicsbody in a minimally invasive manner.

FIG. 13A is a side schematic view of an analyte sensor with anchoringmaterial on a first and second major surface of the device, includingthe surface on which the sensing region is located, wherein the analytesensor is implanted subcutaneously and is ingrown with fibrous,vascularized tissue.

13B is a side schematic view of an analyte sensor with anchoringmaterial on a first major surface on which the sensing region islocated, and wherein a second major surface is substantially smooth.

FIG. 14A is a graph showing the percentage of functional sensors from astudy of two different sensor geometries implanted in a host.

FIG. 14B is a graph showing the average R-value of sensors from a studyof two different sensor geometries implanted in a host.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description and examples illustrate some exemplaryembodiments of the disclosed invention in detail. Those of skill in theart will recognize that there are numerous variations and modificationsof this invention that are encompassed by its scope. Accordingly, thedescription of a certain exemplary embodiment should not be deemed tolimit the scope of the present invention.

Definitions

In order to facilitate an understanding of the disclosed invention, anumber of terms are defined below.

The term “analyte,” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, to refer to a substanceor chemical constituent in a biological fluid (for example, blood,interstitial fluid, cerebral spinal fluid, lymph fluid or urine) thatcan be analyzed. Analytes may include naturally occurring substances,artificial substances, metabolites, and/or reaction products. In someembodiments, the analyte for measurement by the sensor heads, devices,and methods is glucose. However, other analytes are contemplated aswell, including but not limited to acarboxyprothrombin; acylcarnitine;adenine phosphoribosyl transferase; adenosine deaminase; albumin;alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle),histidine/urocanic acid, homocysteine, phenylalanine/tyrosine,tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers;arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactiveprotein; carbon dioxide; carnitine; carnosinase; CD4; ceruloplasmin;chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase;conjugated 1-β hydroxy-cholic acid; cortisol; creatine kinase; creatinekinase MM isoenzyme; cyclosporin A; d-penicillamine;de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylatorpolymorphism, alcohol dehydrogenase, alpha 1-antitrypsin, cysticfibrosis, Duchenne/Becker muscular dystrophy, glucose-6-phosphatedehydrogenase, hemoglobinopathies, A,S,C,E, D-Punjab, beta-thalassemia,hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber hereditary opticneuropathy, MCAD, RNA, PKU, Plasmodium vivax, sexual differentiation,21-deoxycortisol); desbutylhalofantrine; dihydropteridine reductase;diptheria/tetanus antitoxin; erythrocyte arginase; erythrocyteprotoporphyrin; esterase D; fatty acids/acylglycines; free β-humanchorionic gonadotropin; free erythrocyte porphyrin; free thyroxine(FT4); free tri-iodothyronine (FT3); fiunarylacetoacetase;galactose/gal-1-phosphate; galactose-1-phosphate uridyltransferase;gentamicin; glucose-6-phosphate dehydrogenase; glutathione; glutathioneperioxidase; glycocholic acid; glycosylated hemoglobin; halofantrine;hemoglobin variants; hexosaminidase A; human erythrocyte carbonicanhydrase I; 17 alpha-hydroxyprogesterone; hypoxanthine phosphoribosyltransferase; immunoreactive trypsin; lactate; lead; lipoproteins ((a),B/A-1, β); lysozyme; mefloquine; netilmicin; oxygen; phenobarbitone;phenytoin; phytanic/pristanic acid; progesterone; prolactin; prolidase;purine nucleoside phosphorylase; quinine; reverse tri-iodothyronine(rT3); selenium; serum pancreatic lipase; sissomicin; somatomedin C;specific antibodies (adenovirus, anti-nuclear antibody, anti-zetaantibody, arbovirus, Aujeszky's disease virus, dengue virus, Dracunculusmedinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus,Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpesvirus, HIV-1, IgE (atopic disease), influenza virus, Leishmaniadonovani, leptospira, measles/mumps/rubella, Mycobacterium leprae,Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenzavirus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa, pH,respiratory syncytial virus, rickettsia (scrub typhus), Schistosomamansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosomacruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellowfever virus); specific antigens (hepatitis B virus, HIV-1);succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine(T4); thyroxine-binding globulin; trace elements; transferrin;UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A;white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat,vitamins and hormones naturally occurring in blood or interstitialfluids may also constitute analytes in certain embodiments. The analytemay be naturally present in the biological fluid, for example, ametabolic product, a hormone, an antigen, an antibody, and the like.Alternatively, the analyte may be introduced into the body, for example,a contrast agent for imaging, a radioisotope, a chemical agent, afluorocarbon-based synthetic blood, or a drug or pharmaceuticalcomposition, including but not limited to insulin; ethanol; cannabis(marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide,amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine(crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin,Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine);depressants (barbituates, methaqualone, tranquilizers such as Valium,Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens(phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics(heroin, codeine, morphine, opium, meperidine, Percocet, Percodan,Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogsof fentanyl, meperidine, amphetamines, methamphetamines, andphencyclidine, for example, Ecstasy); anabolic steroids; and nicotine.The metabolic products of drugs and pharmaceutical compositions are alsocontemplated analytes. Analytes such as neurochemicals and otherchemicals generated within the body may also be analyzed, such as, forexample, ascorbic acid, uric acid, dopamine, noradrenaline,3-methoxytyramine (3MT), 3,4-Dihydroxyphenylacetic acid (DOPAC),Homovanillic acid (HVA), 5-Hydroxytryptamine (5HT), and5-Hydroxyindoleacetic acid (FHIAA).

By the terms “evaluated”, “monitored”, “analyzed”, and the like, it ismeant that an analyte may be detected and/or measured. [0109] The terms“sensor head” and “sensing region” as used herein are broad terms andare used in their ordinary sense, including, without limitation, theregion of a monitoring device responsible for the detection of aparticular analyte. In one embodiment, the sensing region generallycomprises a non-conductive body, a working electrode (anode), areference electrode, and a counter electrode (cathode) passing throughand secured within the body forming an electrochemically reactivesurface at one location on the body and an electronic connective meansat another location on the body, and a multi-region membrane affixed tothe body and covering the electrochemically reactive surface. Thecounter electrode generally has a greater electrochemically reactivesurface area than the working electrode. During general operation of thesensor a biological sample (for example, blood or interstitial fluid) ora portion thereof contacts (directly or after passage through one ormore membranes or domains) an enzyme (for example, glucose oxidase); thereaction of the biological sample (or portion thereof) results in theformation of reaction products that allow a determination of the analyte(e.g., glucose) level in the biological sample. In preferredembodiments, the multi-region membrane further comprises an enzymedomain and an electrolyte phase, namely, a free-flowing liquid phasecomprising an electrolyte-containing fluid described further below.While the preferred embodiments are generally illustrated by a sensor asdescribed above, other sensor head configurations are also contemplated.While electrochemical sensors (including coulometric, voltammetric,and/or amperometric sensors) for the analysis of glucose are generallycontemplated, other sensing mechanisms, including but not limited tooptochemical sensors, biochemical sensors, electrocatalytic sensors,optical sensors, piezoelectric sensors, thermoelectric sensors, andacoustic sensors may be used. A device may include one sensing region,or multiple sensing regions. Each sensing region can be employed todetermine the same or different analytes. The sensor region may includethe entire surface of the device, a substantial portion of the surfaceof the device, or only a small portion of the surface of the device.Different sensing mechanisms may be employed by different sensor regionson the same device, or a device may include one or more sensor regionsand also one or more regions for drug delivery, immunoisolation, celltransplantation, and the like. It may be noted that the preferredembodiments, the “sensor head” is the part of the sensor that houses theelectrodes, while the “sensing region” includes the sensor head and areathat surrounds the sensor head, particularly the area in such proximityto the sensor head that effects of the foreign body capsule on thesensor head.

The term “foreign body capsule” or “FBC,” as used herein, is a broadterm and is used in its ordinary sense, including, without limitation,body's response to the introduction of a foreign object; there are threemain layers of a FBC: 1) the innermost layer, adjacent to the object, iscomposed generally of macrophages, foreign body giant cells, andocclusive cell layers; 2) the intermediate FBC layer, lying distal tothe first layer with respect to the object, is a wide zone (e.g., about30-100 microns) composed primarily of fibroblasts, contractile fibroustissue fibrous matrix; and 3) the outermost FBC layer is looseconnective granular tissue containing new blood vessels. Over time, thisFBC tissue becomes muscular in nature and contracts around the foreignobject so that the object remains tightly encapsulated.

The term “subcutaneous,” as used herein, is a broad term and is used inits ordinary sense, including, without limitation, under the skin.

The term “intramuscular,” as used herein, is a broad term and is used inits ordinary sense, including, without limitation, within the substanceof a muscle.

The term “intraperitoneal,” as used herein, is a broad term and is usedin its ordinary sense, including, without limitation, within theperitoneal cavity, which is the area that contains the abdominal organs.

The term “intrafascial,” as used herein, is a broad term and is used inits ordinary sense, including, without limitation, within the fascia,which is a sheet or band of fibrous tissue such as lies deep to the skinor forms an investment for muscles and various other organs of the body.

The term “axillary region,” as used herein, is a broad term and is usedin its ordinary sense, including, without limitation, the pyramidalregion between the upper thoracic wall and the arm, its base formed bythe skin and apex bounded by the approximation of the clavicle, coracoidprocess, and first rib; it contains axillary vessels, the brachialplexus of nerves, many lymph nodes and vessels, and loose areolartissue.

The term “apex,” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, the uppermost point; forexample the outermost point of a convexly curved portion.

The term “cuboidal,” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, a polyhedron composed ofsix faces, eight vertices, and twelve edges, wherein the faces.

The term “convex,” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, outwardly protuberant;that is, an object is convex if for any pair of points within theobject, any point on the line that joins them is also within the object.A convex portion is a portion of an object that is convex in thatportion of the object. For example, a solid cube is convex, but anythingthat is hollow or has a dent in it is not convex.

The term “curvature,” “curved portion,” and “curved,” as used herein,are broad terms and is used in their ordinary sense, including, withoutlimitation, one or more arcs defined by one or more radii.

The term “cylindrical,” as used herein, is a broad term and is used inits ordinary sense, including, without limitation, a solid of circularor elliptical cross section in which the centers of the circles orellipses all lie on a single line. A cylinder defines a lateral surfaceand two ends.

The term “ellipsoidal,” as used herein, is a broad term and is used inits ordinary sense, including, without limitation, closed surface ofwhich all plane sections are either ellipses or circles. An ellipsoid issymmetrical about three mutually perpendicular axes that intersect atthe center.

The term “spherical,” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, a solid that is boundedby a surface consisting of all points at a given distance from a pointconstituting its center.

The term “anchoring material,” as used herein, is a broad term and isused in its ordinary sense, including, without limitation, biocompatiblematerial that is non-smooth, and particularly comprises an architecturethat supports tissue ingrowth in order to facilitate anchoring of thematerial into bodily tissue in vivo. Some examples of anchoringmaterials include polyester, polypropylene cloth,polytetrafluoroethylene felts, expanded polytetrafluoroethylene, andporous silicone, for example.

The term “mechanical anchoring mechanism,” as used herein, is a broadterm and is used in its ordinary sense, including, without limitation,mechanical mechanisms (e.g., prongs, spines, barbs, wings, hooks,helical surface topography, gradually changing diameter, or the like),which aids in immobilizing the sensor in the subcutaneous space,particularly prior to formation of a mature foreign body capsule

The term “biocompatible,” as used herein, is a broad term and is used inits ordinary sense, including, without limitation, compatibility withliving tissue or a living system by not being toxic.

The term “non-adhesive to tissue,” as used herein, is a broad term andis used in its ordinary sense, including, without limitation, a materialor surface of a material to which cells and/or cell processes do notadhere at the molecular level, and/or to which cells and/or cellprocesses do not adhere to the surface of the material.

The term “plastic,” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, polymeric materials thathave the capability of being molded or shaped, usually by theapplication of heat and pressure. Polymers that are classified asplastics can be divided into two major categories: thermoplastic andthermoset.

The term “thermoplastic,” as used herein, is a broad term and is used inits ordinary sense, including, without limitation, polymeric materialssuch as polyethylene and polystyrene that are capable of being moldedand remolded repeatedly. The polymer structure associated withthermoplastics is that of individual molecules that are separate fromone another and flow past one another.

The term “thermoset,” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, polymeric materials suchas epoxy, silicone, and polyurethane that cannot be reprocessed uponreheating. During their initial processing, thermosetting resins undergoa chemical reaction that results in an infusible, insoluble network.Essentially, the entire heated, finished article becomes one largemolecule. For example, the epoxy polymer undergoes a cross-linkingreaction when it is molded at a high temperature. Subsequent applicationof heat does not soften the material to the point where it can bereworked and indeed may serve only to break it down.

The term “substantially,” as used herein, is a broad term and is used inits ordinary sense, including, without limitation, refers to an amountgreater than 50 percent, preferably greater than 75 percent and, mostpreferably, greater than 90 percent.

The term “host,” as used herein is a broad term and is used in itsordinary sense, including, without limitation, both humans and animals.

The term “R-value,” as used herein, is a broad term and is used in itsordinary sense, including, without limitation, one conventional way ofsummarizing the correlation of data; that is, a statement of whatresiduals (e.g., root mean square deviations) are to be expected if thedata are fitted to a straight line by the a regression.

Overview

In a preferred embodiment, the sensor heads, devices, and methods of thepreferred embodiments may be used to determine the level of glucose orother analytes in a host. The level of glucose is a particularlyimportant measurement for individuals having diabetes in that effectivetreatment depends on the accuracy of this measurement.

Although the description that follows is primarily directed atimplantable glucose sensors, the methods of the preferred embodimentsare not limited to either electrochemical sensing or glucosemeasurement. Rather, the methods may be applied to any implantablesensor that detects and quantifies an analyte present in biologicalfluids (including, but not limited to, amino acids and lactate),including those analytes that are substrates for oxidase enzymes (see,e.g., U.S. Pat. No. 4,703,756 to Gough et al., hereby incorporated byreference), as well as to implantable sensors that detect and quantifyanalytes present in biological fluids by analytical methods other thanelectrochemical methods, as described above. The methods may also offerbenefits and be suitable for use with implantable devices, other thansensors, that are concerned with the transport of analytes, for example,drug delivery devices, cell transplantation devices, tracking devices,or any other foreign body implanted subcutaneously or in other softtissue of the body, for example, intramuscular, intraperitoneal,intrafascial, or in the axial region.

Methods and devices that may be suitable for use in conjunction withaspects of the preferred embodiments are disclosed in copendingapplications including U.S. application Ser. No. 09/916,386 filed Jul.27, 2001 and entitled “MEMBRANE FOR USE WITH IMPLANTABLE DEVICES”; U.S.application Ser. No. 09/916,711 filed Jul. 27, 2001 and entitled “SENSORHEAD FOR USE WITH IMPLANTABLE DEVICE”; U.S. application Ser. No.09/447,227 filed Nov. 22, 1999 and entitled “DEVICE AND METHOD FORDETERMINING ANALYTE LEVELS”; U.S. application Ser. No. 10/153,356 filedMay 22, 2002 and entitled “TECHNIQUES TO IMPROVE POLYURETHANE MEMBRANESFOR IMPLANTABLE GLUCOSE SENSORS”; U.S. application Ser. No. 09/489,588filed Jan. 21, 2000 and entitled “DEVICE AND METHOD FOR DETERMININGANALYTE LEVELS”; U.S. application Ser. No. 09/636,369 filed Aug. 11,2000 and entitled “SYSTEMS AND METHODS FOR REMOTE MONITORING ANDMODULATION OF MEDICAL DEVICES”; and U.S. application Ser. No. 09/916,858filed Jul. 27, 2001 and entitled “DEVICE AND METHOD FOR DETERMININGANALYTE LEVELS,” as well as issued patents including U.S. Pat. No.6,001,067 issued Dec. 14, 1999 and entitled “DEVICE AND METHOD FORDETERMINING ANALYTE LEVELS”; U.S. Pat. No. 4,994,167 issued Feb. 19,1991 and entitled “BIOLOGICAL FLUID MEASURING DEVICE”; and U.S. Pat. No.4,757,022 filed Jul. 12, 1988 and entitled “BIOLOGICAL FLUID MEASURINGDEVICE.” All of the above patents and patent applications areincorporated in their entirety herein by reference.

Such medical devices, including implanted analyte sensors, drug deliverydevices and cell transplantation devices require close vascularizationand transport of solutes across the device-tissue interface for properfunction. These devices generally include a biointerface membrane, whichencases the device or a portion of the device to prevent access by hostinflammatory cells, immune cells, or soluble factors to sensitiveregions of the device.

Nature of the Foreign Body Capsule

Biointerface membranes stimulate a local inflammatory response, calledthe foreign body response (FBR) that has long been recognized aslimiting the function of implanted devices that require solutetransport. The FBR has been well described in the literature.

FIG. 1 is a schematic drawing that illustrates a classical foreign bodyresponse (FBR) to an object implanted under the skin. There are threemain regions of a FBR. The innermost FBR region 12, adjacent to thedevice, is composed generally of macrophages and foreign body giantcells 14 (herein referred to as the barrier cell layer). These cellsform a monolayer of closely opposed cells over the entire surface of amicroscopically smooth, macroscopically smooth (but microscopicallyrough), or microporous (i.e., less than about 1 μm pore size) membrane.The intermediate FBR region 16 (herein referred to as the fibrous zone),lying distal to the first region with respect to the device, is a widezone (about 30-1000 microns) composed primarily of fibroblasts 18,contractile fibrous tissue 19, and fibrous matrix 20 (shown as emptyspace, which is actually filled with this fibrous matrix). It may benoted that the organization of the fibrous zone, and particularly thecontractile fibrous tissue 19, contributes to the formation of themonolayer of closely opposed cells due to the contractile forces 21around the surface of the foreign body (e.g., membrane 10). Theoutermost FBR region 22 is loose connective granular tissue containingnew blood vessels 24 (herein referred to as the vascular zone). Overtime, the foreign body capsule becomes muscular due to differentiationof fibroblasts into myofibroblasts and contracts around the foreign bodyso that the foreign body remains tightly encapsulated.

Sensor Geometry

It has been observed that the variability of function observed inimplanted sensors may sometimes occur in several different devicesimplanted within the same host (e.g., human or animal). Accordingly,this observation suggests that individual variability of hosts may notbe a significant factor in the observed variability. Data suggest that amajor factor in the variability is the individual nature of how thesurrounding tissue heals around each device. Accordingly, the presentinvention discloses methods and systems for selecting an appropriategeometry for a device that requires transport of analytes in vivo, suchthat the healing of the host tissue around the device is optimized.Optimizing the host response includes minimizing variability, increasingtransport of analytes, and controlling motion artifact in vivo, forexample.

FIG. 2A is schematic side view of a prior art device that has a sensingregion with an abrupt inside turn, causing sub-optimal foreign bodyresponse. FIG. 2B is a photomicrograph of the type of device of FIG. 2Aafter formation of the foreign body capsule and subsequent explantation,showing thickened host response adjacent the abrupt inside turn andlymphocytic infiltrate.

Particularly, FIG. 2A depicts a sensor 26 wherein a dome sensor head 28incorporating the sensing electrodes 30 or other sensing devices ormeans protrudes above a large, flat surface 32 of the device.Particularly noteworthy is the abrupt change in curvature of anapproximately 90-degree turn between the sensor head 28 and the flatsurface 32. Additionally, an O-ring 34 encircles the device to hold abiointerface membrane (not shown) over the dome sensor head 28 of thedevice and causes further discontinuity of the surface between thesensor head and the flat surface of the sensor body.

A wide variability in the healing of the tissue adjacent to the sensordome of the device is observed. Particularly, the foreign body capsuleis thickest in the area 42 adjacent to the discontinuous surface (e.g.,O-ring and sensor head-sensor body interface). This thickest portion isa result of tissue contracture that occurs during the foreign bodyresponse, resulting in forces being applied to the portion of the deviceinterfacing with the tissue. Notably, because the device of FIG. 2A hasan inside turn where the dome meets the top plate at the O-ring, theforces 40 exerted by contracture pull outwards, and thus away from thedevice-tissue interface. This causes inflammation in the region of theinside turn. Greater tissue trauma and the formation of barrier celllayers are typically observed adjacent to the region of the devicewherein the dome meets the top plate. It is believed that outward forcesproduced by tissue contraction cause wounding in this site, whichstimulates higher levels of inflammation, resulting in occlusion. Itshould be noted that this more “turbulent area” 42 is marked by anincrease chronic inflammatory response which is most occlusive at thediscontinuous surface are, but spreads to include the thickening insensing area 41 that may effect the transport of analytes and thus thefunction of the sensor in vivo.

FIG. 2B is a photomicrograph of the foreign body capsule, after a devicehaving the sensor configuration of FIG. 2A was explanted from a host.The right side of the photomicrograph shows a thickening of the tissueresponse with inflammatory cells present near the inside turn (within44). The o-ring 34 was located approximately as shown by the dashedline, which contributed to the thickening of the tissue response due tothe abruptness of the surface area. It may be noted that the tissueresponse thins near the center of the dome (at 46 (the fold in thesection near the center of the dome is an artifact of samplepreparation)). The electrodes are located within the sensing region 47as shown on the photomicrograph, over which occlusive cells extend fromthe thickened response 44. That is, the thickening of the tissues in the“turbulent area”, which is the area adjacent to the discontinuoussurfaces at the inside turn, leads to the subsequent formation ofbarrier cell layers that may continue over the sensor head and block thetransport of analytes across the device-tissue interface over time. Thenature of the response suggests that trauma to the tissue may haveoccurred during or after the initial wound healing. If trauma occursduring wound healing, complete healing never occurs and the tissue staysin a hyper-inflammatory state during the entire course of the implantperiod. Alternatively, if trauma occurs subsequent to the initial woundhealing, the wound heals but is re-injured, perhaps repeatedly, overtime. Either of these trauma-induced wounding mechanisms may lead toimproper healing and the growth of occlusive cells at the biointerface.It may be noted that it is the combination of the severity of the insideturn and its proximity to the sensing region that forms the occlusivecell layer, which may cause blockage of analyte transport to the sensor.In some alternative embodiments, certain turns (e.g., inside turns orotherwise) on the surface of the sensor body may not adversely effectthe transport of analytes; for example, turns that are located at asufficient distance from the sensing region may not produce a thickenedinflammatory host response adjacent the sensing region and/or turns thatare sufficiently gradual and/or lack abruptness may not adversely effectthe host response adjacent the sensing regions.

The tissue response resulting in the growth of occlusive cells asdescribed above tends to occur due to the contraction of the surroundingwound tissue. It is therefore desirable to ensure stable wound healingthat does not change after the initial healing. As illustrated by thephotomicrograph of FIG. 2B, the geometry of the device depicted does notfavor stable healing because tissue contracture results in the pullingaway of tissues from the device surface at the junction between the domeand top plate.

FIG. 3A is a schematic side view of another prior art device that hasflattened surfaces across the entire device, and particularly across thesensing region, creating sub-optimal foreign body capsule healing. Inthe sensor of FIG. 3A, all surfaces are flat and all edges and cornersare sharp; there is no curvature or convexity, particularly in thesensing region.

Consequently, contractile forces 54 pull laterally and outwardly alongthe flat surfaces, including the sensing region, which is the areaproximal to the electrodes 52, as the FBC tightens around the device.Lateral contractile forces 54 caused by the FBC 50 along the flatsurfaces are believed increase motion artifact and tissue damage due toshear forces 56 between the device 52 and the tissue. In other words,rather than firmly holding the tissue adjacent the sensing region with adownward force against the sensing region (such as will be shown withthe geometry of the present invention), a lateral movement (indicated byarrow 56) is seen in the tissue adjacent to the sensing region, causingtrauma-induced wounding mechanisms that may lead to improper healing andthe growth of occlusive cells at the biointerface. This is especiallyharmful in the sensing region, which requires substantially consistenttransport of analytes, because it is known that thickening of the FBCfrom chronic inflammation and occlusive cells decreases or blocksanalyte transport to the device.

It may be noted that some prior art devices attempt to minimize tissuetrauma by rounding edges and corners, however the effects of tissuetrauma will still be seen in the flat surfaces (e.g., sensing region) ofthe device such as described above, thereby at least partiallyprecluding function of a device requiring analyte transport. Similarly,placement of the sensing region, or a plurality of sensing regions, awayfrom the center of the device (such as seen in some prior art devices)would not significantly improve the effects of the lateral contractileforces along the flat surface of the sensing region(s), because it isthe flat surface, whether at the center and/or off center, that causesin the occlusive tissue trauma in vivo.

It may be noted that the thickness of the FBC appears to increase aroundthe central portion of the device and be thinner around the ends. It isbelieved that this phenomenon is due to the loose and counteractinglateral contractile forces near the center of the device, while atighter contractile force near the ends of the device indicates tightercontrol of the FBC.

FIG. 3B is a schematic side view of the sensing region of yet anotherprior art device that has flattened surfaces across the device, howeverincludes an inset sensing region. The device of FIG. 3B is similar tothe device of FIG. 3A, and is another example of a disadvantageousdevice due to sub-optimal foreign body capsule healing. Particularly,the inset portion 58, whether bounded by sharp or rounded edges, willcause contractile forces 54 of the foreign body capsule to pulloutwardly and laterally. The inset region of the device will experienceincreased trauma-induced wounding mechanisms that may lead to improperhealing and the growth of occlusive cells at the biointerface ascompared to FIG. 3A. In other words, both flat and inset (e.g., concave)sensing regions will cause tissue wounding and chronic inflammatoryresponse leading to decreased transport of analytes, increased time lag,and decreased device function.

In contrast to the prior art, a preferred embodiment of the presentinvention provides a sensor geometry that includes a sensing regionadapted for transport of analytes between the sensor and the bodilyfluid, wherein the sensing region is located on a curved portion of thesensor body such that when a foreign body capsule forms around thesensor, a contractile force is exerted by the foreign body capsuletoward the sensing region. This contractile force provides sufficientsupport to maintain the foreign body capsule in close proximity to thesensing region without substantial motion artifact or shearing forces,thereby minimizing inflammatory trauma, minimizing the thickness of theforeign body capsule, and maximizing the transport of analytes throughthe foreign body capsule. Additionally, the overall design describedherein ensures more stable wound healing, and therefore betteracceptance in the body.

It may be noted that the disadvantageous outward forces (e.g., forces 40as described with reference to FIG. 2A, and forces 54 such as describedwith reference to FIG. 3B) refer to forces that cause motion of theforeign body capsule relative to the device as a whole. In other words,the discontinuity of the surface on which the sensing region is locatedcreates outward forces of the FBC as a whole, which unfortunately allowsmotion of the device within the FBC. These outside forces 40 create athickened FBC due to chronic inflammatory response responsive to motionof the device within the FBC such as described with reference to FIGS. 2and 3. It may be noted however that a biointerface material withinterconnected cavities in at least a portion thereof may be placed overthe sensor head such as described with reference to copending U.S.patent application Ser. No. 10/647,065 filed Aug. 22, 2003 and entitled“POROUS MEMBRANE FOR USE WITH IMPLANTABLE DEVICES”, which isincorporated herein in its entirety by reference. This biointerfacematerial advantageously causes disruption of the contractile forcescaused by the fibrous tissue of the FBC within the cavities of thebiointerface material. Particularly, the biointerface material includesinterconnected cavities with a multiple-cavity depth, which may affectthe tissue contracture that typically occurs around a foreign body. Thatis, within the cavities of the biointerface material, forces from theforeign body response contract around the solid portions that define thecavities and away from the device. This architecture of theinterconnected cavities of the biointerface material is advantageousbecause the contractile forces caused by the downward tissue contracturethat may otherwise cause cells to flatten against the device and occludethe transport of analytes, is instead translated to and/or counteractedby the forces that contract around the solid portions (e.g., throughoutthe interconnected cavities) away from the device. Therefore, themechanisms of the present invention (e.g., geometric configurationsdescribed herein) are designed to increase downward forces on the sensorhead in order to decrease motion of the device relative to the FBC as awhole, which complements the mechanisms of the biointerface materialthat causes disruption of the contractile forces within the biointerfacematerial in order to deflect the forces toward the solid portions withinthe biointerface and away from the device itself, both of whichmechanisms work to prevent the formation of occlusive cells that blockanalyte transport. Therefore, a biointerface material such as describedabove may be placed over at least a portion (e.g., some or all) of thesensing region of the devices of the present invention to aid inpreventing the formation of occlusive cells (e.g., barrier cell layer)and increasing the transport of analytes.

FIG. 4 is a cross-sectional view of the sensing region of an analytesensor in one embodiment, wherein the sensing region is continuouslycurved, thereby causing contractile forces from the foreign body capsuleto press downward thereon. The sensing region is located on an end ofsensor that extends longitudinally (not shown). Particularly, the curvedsensor region 70 includes no abrupt edges or discontinuous surfaces toensure stable wound healing. For example, such a device 68 may becylindrical with a collet that meets the head, as depicted in FIG. 4.The collet produces a continuous curvature from the sensor dome 72 tothe wall of the cylinder 73. When this design is employed, tissuecontracture (depicted by the arrows 74) results in forces oriented intowards the device interface along the entire surface of the dome(depicted by arrows 76). Thus, the foreign body capsule is pulled downagainst the surface of the device. Injury and re-injury is therebyminimized or even prevented because there are no outward forces producedby tissue contracture as in the design depicted in the devices of FIGS.2 and 3. Improved biointerface healing is observed for this geometry, asevidenced by improved in vivo performance. A device with a designsimilar to that depicted in FIG. 4 was the subject of animal testing,which is described in more detail with reference to FIGS. 11A and 11B.

FIG. 5A is a perspective view of an analyte sensor in anotherembodiment, including a thin ellipsoidal geometry, a curved sensingregion, and an overall curved surface on which the sensing region islocated, thereby causing contractile forces from the foreign bodycapsule to press downward on the sensor head. FIG. 5B is the analytesensor of FIG. 5A shown implanted with the sensing region adjacent tothe muscle fascia underlying the subcutaneous space. FIG. 5C is an endview of the analyte sensor of FIG. 5A showing the contractile forcesthat would be caused by a foreign body capsule. FIG. 5D is a side viewof the analyte sensor of FIG. 5A.

In this embodiment, the analyte sensor 80 includes the sensing region 82located on a curved portion of the sensor body, and including no abruptedge or discontinuous surface in the proximity of the sensing region.Additionally, the overall curvature of the surface on which the sensingregion is located, including rounded edges, invokes a generally uniformFBC around that surface, decreasing inflammatory response and increasinganalyte transport at the device-tissue interface 84.

In one aspect of this embodiment, the sensor geometry particularlysuited for healing at the device-tissue interface 84 when the sensor isimplanted between two tissue planes. That is, the geometry includes athin, substantially oval sensor, wherein the sensor head is positionedon one of the major surfaces of the sensor rather than at the tip, asillustrated in FIG. 4. When implanted, the sensor is oriented such thatthe sensor head is adjacent to the fascia underlying the subcutaneousspace.

Perpendicular forces 88, depicted in FIG. 5C by arrows pointing down,reduce or eliminate shear forces with the tissue at the sensor head.While lateral forces 90 may appear to create shear forces at the sensorhead, several features of the sensor mitigate these forces. For example,the sensor is much thinner and is immediately adjacent to the fascia,underlying the fat, making it less prone to movement. As anotherexample, the sensor may be sutured to the tough fascia, which furtherprevents lateral forces from being conveyed to the sensor head; while inother preferred embodiments, an anchoring material or other method ofattachment may be employed. As yet another example, in order tofacilitate proper healing, the side of the sensor upon which the sensorhead is situated preferably has a curved radius extending from lateralside to lateral side. As depicted in the side view and end view (FIGS.5C and 5D), the sensor head is positioned at the apex of the radius.When surrounding tissue contracts as it heals, the radius serves tooptimize the forces 88 exerted down onto the curved surface, especiallythe forces in the lateral directions 90, to keep the tissue uniformly incontact with the surface and to produce a thinner foreign body capsule.The curvature ensures that the head is resting against the tissue andthat when tissue contraction occurs, forces are generated downward onthe head so that the tissue attachment is maintained. It may be notedthat the downward forces bring the tissue into contact with porousbiointerface materials used for ingrowth-mediated attachment and forbiointerface optimization, such as described above and in copending U.S.patent application Ser. No. 10/647,065 filed Aug. 22, 2003 and entitled“POROUS MEMBRANE FOR USE WITH IMPLANTABLE DEVICES”. While it ispreferable to have a curved radius extending longitudinally, in certainembodiments it may be acceptable to incorporate a longitudinally flatsurface or longitudinal surface with another configuration. In a deviceas depicted in FIG. 5C, the radius of curvature in the lateral directionis preferably about 2.7 cm.

It may be noted that any curved surface can be deconvoluted to a seriesof radii, as is appreciated by one skilled in the art. It is generallypreferred to have a radius of curvature in the lateral, longitudinal orother direction of from about 0.5 mm or less to about 10 cm or more.More preferably the radius of curvature is from about 1, 2, 3, 4, 5, 6,7, 8, or 9 mm to about 5, 6, 7, 8, or 9 cm, even more preferably theradius of curvature is from about 1, 1.25, 1.5, 1.75, 2 or 2.25 cm toabout 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, or 4.75 cm, and most preferablythe radius of curvature is from about 2.5 or 2.6 cm to about 2.7, 2.8,or 2.9 cm. Radii of curvature in the longitudinal direction aregenerally preferred to be larger than those in the lateral direction.However, in certain embodiments the radii of curvature may beapproximately the same, or smaller in the longitudinal direction.

In one embodiment, the preferred shape of the device can be defined inthe context of a reference plane. In such an embodiment, the device hasa first major surface and a second major surface opposite the firstmajor surface, where the first major surface includes a sensor. Thefirst and second major surfaces together preferably account for at leastabout 40% or 50% of the surface area of the device. The first majorsurface has edges between which a width of the first major surface canbe measured, and the sensor is preferably spaced away from the edges bya distance that is at least about 10% of the width, and preferably atleast about 15%, 20%, 25%, or 30% of the width of the first majorsurface. It is understood that the first major surface may have multipleedges and that multiple widths can be measured, and in the context ofthe foregoing, a width should be configured to run from one edge to anopposite edge. Preferably, spacing of the sensor from the edgesspecified above is true for at least two width measurements, whichmeasurements are taken generally transverse to each other.

With the sensor situated on the first major surface of the device, areference plane can be imagined that is congruent to the first majorsurface, which first major surface is preferably at least slightlyconvex. This plane, which would then touch the first major surface at apoint spaced in from the edges of the first major surface, would begenerally parallel to the first major surface and would additionally bespaced away from opposite edges of the first major surface due to theconvex nature of the first major surface. In preferred embodiments, thereference plane would be spaced from the edges a distance that is atleast about 3%, 4%, or 5% of the width between those edges, and morepreferably 6%, 7%, 8% or more from the edges, but at the same time thedistance is preferably not more than 50%, 40%, or 30% of the width, andmay well be not more than 25 %, 20 %, or 15 % of the width between theedges. In preferred embodiments, the edges of the first major surfaceare rounded, so that they transition smoothly away from the first majorsurface. In this situation, the location of the edge can be configuredto be the point at which a congruent line and/or a normal line would beangled 45 degrees with respect to the reference plane.

In preferred embodiments, the sensor body defines a surface area, andwherein between 10% and 100% of the surface area is convexly curved. Insome preferred embodiments a substantial portion of the surface area isconvexly curved. In one preferred embodiment, at least about 90% of thesurface area is convexly curved. In other preferred embodiments, 10, 20,30, 40, 50, 60, 70, 80, 90, or 100% of the surface area is curved.

FIG. 6 is a perspective view of a sensor geometry in an alternativeembodiment wherein the sensor includes a curved sensor region and a flatregion, wherein the interface between the flat region and the curvedregion includes a gradual transition. The implantable sensor includes amajor surface 100 with a curved portion 102 on which the sensing region101 is located and a flat portion 104 adjacent to the curved portion102. Although the major surface is not entirely curved in thisembodiment, the interface 103 between the curved and flat portions has agradual transition and is located sufficiently distal from the sensingregion 101 (where the transport of analytes is required) that anychronic inflammation caused by the turn at the interface 103 will notlikely translate to the sensing region 101. In other words, thecontractile forces 106 from a foreign body capsule that forms around thesensor in vivo will tend to contract toward the sensing region 101;although some outward and lateral forces are seen at the interface 103and flat surface 104, they are spaced sufficiently far from the sensingregion such that any chronic inflammatory response will not likely coverthe sensing region 101 and block analyte transport. Anchoring materialmay cover some part or the majority of the major surface 100, mayencircle the circumference of the sensor body 107, and/or may cover somepart or the entire surface 108 opposite the sensing region, such asdescribed in more detail elsewhere herein.

FIG. 7 is a perspective view of a sensor geometry in an alternativeembodiment wherein the entire sensor body is curved. The implantablesensor has a curvature over the entire surface area of the sensor body110. The curvature includes a variety of different radii at varyinglocations of the sensor body, and the contractile forces 112 from a FBCthat forms around the sensor in vivo will tend to contract toward theentire sensor body 110, including the sensing region 114 on a firstmajor side 116. Accordingly, this embodiment optimizes foreign bodyhealing by minimizing the chronic inflammatory response that isotherwise caused by motion within the FBC. In other words, the FBC holdstightly to the sensor body 110 to provide optimal control (e.g., minimalmotion) of the tissues around the sensor geometry, and particularlyaround the sensing region 112. It may be noted that the second majorside 118 has a slight curvature that allows the entire sensor body to becurved. However in some embodiments, the second major side 118 can bedesigned flat rather than curved; in these embodiments, it may be notedthat the sensing region is located on the side opposite the flat surfaceand there is no concavity therein or thereon. Anchoring material maycover some part or a majority of the first major side 116, may encirclethe circumference of the sensor body 1 17, and/or may cover some part orthe entire second major side 118 opposite the sensing region.

FIG. 8 is a perspective view of a sensor 120 in an alternativeembodiment including a cylindrical geometry wherein a plurality ofsensors 124 are located on the curved lateral surface 122 of the sensorbody. Anchoring material (not shown) may cover at least some of thenon-electrode surface area of the cylindrical body. The sensor of thisembodiment takes advantage of numerous features described herein,including, but not limited to, the following advantages.

As a first noted advantage, the cylindrical geometry of the sensor body120 allows for discreet placement within or between tissue types whenthe overall surface area-to-volume ratio can be optimized to provide amaximal surface area with a minimal volume. That is, although the volumeof a sensor often depends on the necessary electronics within the sensorbody, the evolution of smaller batteries and circuit boards sanctionsthe design and manufacture of a cylindrical sensor with minimal volume;simultaneously, the surface area inherent in a cylindrical geometryallows for maximal tissue anchoring in vivo (e.g., as compared to asubstantially rectangular or oval structure). In one exemplaryembodiment, an application specific integrated circuit (ASIC) may bedesigned to fit within the geometric design of any of the embodimentsdisclosed herein to maximize the electronic capabilities whileminimizing volume requirements as compared to conventional circuitboards. Sensor electronics requirements vary depend on the sensor type,however one example of electronics for a glucose sensor is described inmore detail with reference to copending U.S. patent application Ser. No.10/633,367 filed on Aug. 1, 2003 and entitled “SYSTEM AND METHODS FORPROCESSING ANALYTE SENSOR DATA,” which is incorporated by referenceherein in its entirety.

As a second rioted advantage, the curved lateral surface 122 of thecylindrical structure lends itself to a plurality of sensing regions 124(e.g., electrodes) and allows the sensor to sense a variety of differentconstituents (e.g., glucose, oxygen, interferants (e.g., ascorbate,urate, etc.)) using one compact sensor body.

As a third noted advantage, when the plurality of sensing regions 124are configured to sense the same constituent (e.g., glucose) such asshown in FIG. 8, and are spread apart such as shown in FIG. 8, thelikelihood of sensor location adjacent an area of the FBC that isoptimized for transport of analytes is increased by the amount ofincrease of the area of the sensing regions 124. For example,inflammatory host response sometimes forms unevenly, therefore adistribution and increased surface area of sensing region(s) increasesthe likelihood of placement of the sensing region adjacent an area ofminimum inflammatory host response and maximum transport of analytes tothe sensor.

As a fourth noted advantage, the FBC that forms around the lateralcurved surface 122 will create generally uniform forces 126 toward thesensing region 124 and around the entire lateral surface. Furthermore,when the ends 128 of the cylindrical sensor body 120 are designed with acurvature such as shown in the embodiment of FIG. 8, minimal chronicinflammatory foreign body response, and further induce a firm,substantially motion-free hold of the sensor body 120 within the host.

FIG. 9A is a perspective view of a sensor geometry in an alternativeembodiment including a substantially spherical body. The sphericalsensor body 130 a has a plurality of sensing regions 132 a that encirclethe body. However, in some alternative embodiments one or more sensingregions may be provided in a collective location or spread across thesurface area of the sphere. Anchoring material is placed on or aroundthe sensor body; for example, the anchoring material 136 a may encirclethe body in a manner similar to that of the sensing regions 132 a. Theembodiment of FIG. 9 takes advantage of numerous features describedherein, including, but not limited to, the following advantages.

As a first noted advantage, a spherical geometry defines an optimalsurface-to-volume ratio when compared to other geometries of deviceswith a comparable volume (e.g., rectangular, oval, and cylindrical).That is, when volume is a constant, the spherical geometry will providean optimal surface area for tissue ingrowth in vivo in combination withan optimal curvature for uniform contractile forces from a FBC in vivoas compared to other geometries.

As a second noted advantage, entirely curved surface area of thespherical geometry lends itself to a plurality of sensing regions (e.g.,electrodes) 132 a and allows the sensor to sense a variety of differentconstituents (e.g., glucose, oxygen, interferants (e.g., ascorbate,urate, etc.)) using one compact sensor body 130 a.

As a third noted advantage, when a plurality of sensing regions 132 athat sense the same constituent (e.g., glucose) are spread apart, thelikelihood of finding an area of the FBC that is optimized for transportof analytes is increased by the amount of increase of the area of thesensing regions.

As a fourth noted advantage, the FBC that forms around the sphericalsensor body will create uniform forces 134 a toward the entire surfacearea, including the sensing regions 132 a, which may therefore belocated anywhere on the sensor body. Consequently in vivo, a sensor bodywith a curvature such as shown in the embodiment of FIG. 9A will induceminimal chronic inflammatory foreign body response, and further induce afirm, substantially motion-free hold of the sensor body within the host.

FIG. 9B is a perspective view of a sensor geometry in an alternativeembodiment including a substantially spherical body with a rod extendingtherefrom. The spherical sensing body 130 b has a plurality of sensingregions 132 b and anchoring material 136 b that encircle (or may beotherwise located on) the body such as described with reference to FIG.9A. However, in contrast to the embodiment of FIG. 9A, a rod 138 isconnected to the spherical body 130 b and houses some or all of thesensor electronics, which are described with reference to FIG. 8. Theembodiment of FIG. 9B takes advantage of numerous features describedherein, including those advantages described with reference to FIG. 9A,and further includes the following advantages.

The separation of at least some of the electronics between the sensingbody which houses the electrodes, from the rod which may house, forexample a cylindrical battery, allows for optimization of the sensingbody design by minimizing the volume and/or mass requirements of thesensing body 130 b due electronics. The geometric design of the sphereand rod as shown in FIG. 9B enables good formation of a FBC because allsurfaces, particularly on the sensing body 130 b) are curved, and thereare not abrupt or flat turns or edges; that is, the contractile forcescreated by the FBC will be exerted generally uniformly toward at leastthe sensing body, and notably toward the sensing region 132 b.Additionally, the sensing regions 132 b are optimally located on acurved area that can be designed with maximum surface area and minimummass and/or volume (e.g., some or all sensor electronics account formuch of the mass and/or volume are located within the rod). It may benoted that in some alternative embodiments, the rod is removablyattachable to the sensing body in vivo such that the electronics and/orsensing body may be individually removed and replaced (e.g., viaminimally invasive methods).

FIGS. 10A to 10D are perspective views of a sensor that has anexpandable sensing body in one embodiment. FIGS. 10A and 10C are viewsof the sensor with the sensing body in a collapsed state, FIGS. 10B and10D are views of the sensor with the sensing body in an expanded state.An expandable sensor 140 is advantageous in that it can be inserted intothe subcutaneous space in a minimally invasive manner (e.g., through acatheter) in its collapsed state. It may be, for example, less than orequal to about 3 mm in diameter 142 and may be designed with a guidewire (not shown) extending through the sensor in some embodiments. Onceit has been delivered into the appropriate site in vivo, the sensingbody expands to an increased surface area.

The sensor 140 includes a sensing body 144 on which the sensing region145 is located and an electronics body 146 in which the sensorelectronics are located such as described with reference to FIG. 8. Inalternative embodiments, some portion of the electronics may be housedwithin the sensing body. The sensing body 144 is formed from anelastomeric material and adapted for expansion using a liquid (e.g.,saline or silicone oil). As an alternative, the sensing body 144 may beformed from a non-elastomeric material (e.g., polyethyleneterephthalate) and folded for insertion using a catheter (not shown). Asanother alternative, the sensing body can be formed from nitinol, or thelike, which may be advantageous due to its ability to self-expand andmemorize its shape long term. In some embodiments, the expandablesensing body is adapted to fill a particular subcutaneous pocket withoutleaving spaces in the subcutaneous space and without causing pressurenecrosis. In one example a metal framework may be used to hold thesensing body in its expanded state. The sensing region 145 includeselectrodes, which are connected to the electronics body via a flexiblewire or the like (not shown). Anchoring material 148 encircles (or isotherwise located on) the sensing body 144 in order to anchor thesensing body stably in vivo. The sensor electronics portion may beformed with or without a curvature, with or without anchoring material,and with or without particular concern for its effect on the foreignbody capsule in vivo as it relates to the sensing body. Additionaladvantages of this embodiment correspond to the advantages describedwith reference to FIG. 9B due to its substantially similar configurationin its expanded state.

FIGS. 11A to 11D are perspective views of sensors wherein one or moresensing bodies are tethered to an electronics body in a variety ofalternative embodiments. In each of the embodiments, the sensor 150includes a sensing body 152 with a sensing region 153 located on acurved portion of the sensing body 152 such that when a foreign bodycapsule forms around the sensing body 152, the foreign body capsuleexerts a contractile force toward the sensing region 153 as describedelsewhere herein. Anchoring material 154 is located on at least aportion of the sensing body 152 in any known manner such as describedelsewhere herein. Furthermore, in each of these embodiments, theelectronics body 156 may include the majority of the mass of the sensor150, which is remote from the sensing body 152. The electronics body 156is connected to the sensing body 152 via a tether 158, which may have avariety of configurations such as described herein. As an alternative tothe tether, the electronics body 156 may be connected to the sensingbody 152 via a wireless RF connection (not shown) such that theelectronics body 156 and the sensing body 152 may be separatelyimplanted, explanted, monitored, and/or replaced. It may be noted thatin an embodiment that utilizes RF transmission to connect the sensingbody to the electronics body, some electronics are housed in the sensingbody 152 to enable measurement and transmission of sensor information.Additionally, in some alternative embodiments of the tethered sensor, atleast some of the electronics are housed within the sensing body.

In these embodiments wherein the sensing body 152 is tethered to theelectronics body 156, the sensing body 152 can be easily optimized forsurface area, shape, size, geometry, mass, density, volume, surfacearea-to-volume, surface area-to-density, and surface area-to-mass asdesired. That is, without the mass, size, and volume constraintsnormally imposed by the electronics portion of a sensor, the sensingbody can be optimally designed for a particular implantation site,function, or other parameter. Additionally, the electronics body can beformed from any biocompatible material (e.g., metal, ceramic, orplastic) known in the art. Additionally, it may be hermetically sealedto protect the electronic components. The tether 158 may be formed froma polymeric material or other biocompatible material and encases aconductive wire (e.g., copper) that connects the electronics within theelectronics body 156 to the electronics portion of the sensing body 152(e.g. to electrodes on the sensing region 153).

This tethered sensor design of these embodiments advantageously allowsfor an optimal design of the sensing body without concern for theeffects of the foreign body response caused by the electronics body. Thetether can be design shorter or longer, and stiffer or more flexible, inorder to optimize the isolation, strain relief, and/or implantationissues.

FIG. 11A illustrates a tethered sensor 150 a includes a sensing body 152a, a flexible tether 158 a, and an electronics body 156 a. In thisexemplary embodiment, the sensing body 152 a is disk-like with a curvedsurface on which the sensing region 153 a is located. An anchoringmaterial 154 a encircles the sensing body for anchoring to the tissue.The tether acts as a strain relief, isolating the adverse effects of theFBC that forms around the electronics body 156 a from the FBC that formsaround the sensing body 152 a.

FIG. 11B illustrates an alternative tethered sensor 150 b that includesa sensing body 152 b, a flexible tether 158 b, and an electronics body156 b. In this exemplary embodiment, the sensing body 152 b comprises acylindrical body with the sensing region 153 b on a curved end. Thetether 158 b is formed from a flexible material and may be formedshorter or longer to adapt to an implantation site. It may be noted thata longer tether may better isolate the adverse effects of the FBC thatforms around the electronics body 156 b from the FBC that forms aroundthe sensing body 152 b, however a shorter tether may simplify theimplantation considerations.

FIG. 11C illustrates an alternative tethered sensor 150 c that includesa sensing body 152 c, a tether 158 c, and an electronics body 156 c. Inthis exemplary embodiment, the tether may be formed from a slightlyflexible to somewhat rigid material. A more rigid material may beadvantageous in controlling the positioning of the sensing body 152 c invivo, a more flexible material may act as a better strain relief invivo.

FIG. 11D illustrates an alternative tethered sensor 150 d that includesa plurality of sensing bodies 152 d, a tether 158 d, and an electronicsbody 156 d. In this exemplary embodiment, the plurality of sensingbodies 152 d with sensing regions on a curved portion of the sensingbody and anchoring material such as described elsewhere herein, howevermay provide additional advantages including for example, the ability toremotely turn on/off one or more of the sensing bodies 152 c, theability to determine which sensing body 152 d is performing moreoptimally and/or consistently for optimizing accuracy and implantationsite, and the ability to have a “back up” sensing body 152 d in theevent one or more of the sensing bodies fails to function as required.

FIGS. 12A to 12B are perspective views of a sensor in an alternativeembodiment wherein an electronics body is independent of the sensingbodies in a preassembled state and wherein the sensing bodies areindependently inserted (and operatively connected) to the electronicsbody in a minimally invasive manner. Particularly, FIG. 12A illustratesthe sensor wherein all four sensing bodies have been inserted and lockedwithin the ports of the electronics body; FIG. 12B includes a cut-awayportion to illustrate how the sensing body locks into electrical contactwithin a port of the electronics body. In this embodiment, the sensor160 includes a plurality of independent sensing bodies 162, alsoreferred to as biointerface probes, and include any necessary components(e.g., electrodes, biointerface materials, etc.) to sense an analyte ofinterest. The sensing bodies 162 further comprise electrical contacts164 that allow the sensing bodies to operatively connect (and lock)within the multiple (optionally inclined) ports 166 of the electronicsbody 168. The sensing bodies 162 may be somewhat flexible and configuredwith a curvature and anchoring material such as described elsewhereherein.

In practice, the electronics body 168 may be implanted in thesubcutaneous tissue without particular concern for the design (e.g.,anchoring material, curvature, etc) and its effect on the formation of aFBC. After the FBC has healed around the electronics body 168, thesensing bodies 162 can be individually inserted in a minimally invasivemanner (e.g., guide wire introduced with needle and sheath) as needed.Advantageously, each sensing body 162 functions up to about one year ormore in vivo. Accordingly, when a sensing body fails to function asneeded, another sensing body 162 may be inserted into another port 166of the electronics body 168.

It may be noted that the sensors of preferred embodiments may be rigidor flexible, and of any suitable shape, including but not limited torectangular, cylindrical, square, elliptical, oval, spherical, circular,ellipsoidal, ovoid, hourglass, bullet-shaped, porpoise-nosed, flatsheet, accordion, or any other suitable symmetrical or irregular shape.Corners may range from sharp to slightly round, to substantially round.While the sensors of preferred embodiments are preferably employed todetermine the presence of an analyte, devices of preferred geometriesmay also be constructed for drug delivery, immunoisolation, celltransplantation, and the like. For example, the preferred deviceconfigurations can be suitable for use in fabricating an artificialpancreas.

In addition to a simple circular curvature, the curvature can also beelliptical or parabolic. The curvature can be perfectly symmetricalabout the sensor head, or can possess some degree of asymmetry. While atrue curvature is generally preferred, in certain embodiments atriangular profile or other polygonal profile with rounded edges mayalso be employed. While a smooth surface is generally preferred, incertain embodiments it may be desired to incorporate local features,such as bumps, dimples, ridges, and the like, while maintaining anoverall curvature. It is generally preferred that each surface isconvex, or less preferably flat but not concave. However, in certainembodiments a slightly concave or recessed surface may be acceptablepresuming it is located sufficiently far from the sensing region thatany chronic inflammatory response will not translate to the areaadjacent the sensor head. The sensor head preferably protrudes above theradius of curvature or is flush with the radius of curvature. A recessedsensor head is generally not preferred. However, in certain embodimentssuch a configuration may be acceptable.

The sensor head may be positioned on any convenient location of on thedevice. Particularly preferred locations are the geometric center of asurface of the device, or offset to one side. In certain embodiments itmay be desirable to incorporate multiple sensor heads on a singledevice. Such sensor heads may be spaced apart so as to maximize thedistance between the sensor heads, or grouped together at one locationon the device.

Manufacture of Sensor Body

In a preferred embodiment, the sensor is formed by substantiallyentirely epoxy encapsulating the sensor electronics; that is, the sensorbody, outside the sensor head, is comprises an epoxy resin body. Duringthe manufacture of the sensor body of the preferred embodiment, thesensitive electronic parts (e.g. battery, antenna, and circuit board,such as described in copending U.S. patent application Ser. No.10/633,367 filed on Aug. 1, 2003 and entitled “SYSTEM AND METHODS FORPROCESSING ANALYTE SENSOR DATA”) are substantially entirely encapsulatedin epoxy, with the exception of the sensor head. In some moldingprocesses, the epoxy body may be formed with a curvature on a portionthereof. After the epoxy has completely cured, additional curvature maybe machined, milled, laser-etched, or otherwise processed into the epoxybody to form the final geometric shape. In alternative embodiments, alight epoxy coating may be applied to the sensitive electronic parts,after which injection molding or reaction injection molding (RIM) may beused to form the final shape of the epoxy body. While a preferred sensoris constructed of epoxy resin, a non-conductive metal, ceramic or othersuitable material may be used.

Anchoring Material & Implantation

In one embodiment, the entire surface of the sensor is covered with ananchoring material to provide for strong attachment to the tissues. Inanother embodiment, only the sensor head side of the sensor incorporatesanchoring material, with the other sides of the sensor lacking fibers orporous anchoring structures and instead presenting a very smooth,non-reactive biomaterial surface to prevent attachment to tissue and tosupport the formation of a thicker capsule. The anchoring material maybe selected from the group consisting of: polyester, polypropylenecloth, polytetrafluoroethylene felts, expanded polytetrafluoroethylene,and porous silicone.

FIG. 13A is a side view of an analyte sensor with anchoring material ona first and second major surface of the device, including the surface onwhich the sensing region is located, wherein the analyte sensor isimplanted subcutaneously and is ingrown with fibrous, vascularizedtissue. FIG. 13B is a side view of an analyte sensor with anchoringmaterial on a first major surface on which the sensing region islocated, and wherein a second major surface is substantially smooth.

While these configurations of anchoring materials are particularlypreferred, other configurations may also be suitable for use in certainembodiments, including configurations with different degrees of surfacecoverage. For example, from less than about 5, 10, 15, 20, 25, 30, 35,40, 45, or 50% to more than about 55, 60, 65, 70, 75, 80, 85, 90, or 95%of the surface of the device may be covered with anchoring material. Theanchoring material may cover one side, two sides, three sides, foursides, five sides, or six sides. The anchoring material may cover only aportion of one or more sides, for example, strips, dots, weaves, fibers,meshes, and other configurations or shapes of anchoring material maycover one or more sides. Likewise, while silicone and polyester fibersare particularly preferred, any biocompatible material capable offacilitating anchoring of tissue to the device may be employed.

It may be noted that the optimum amount of anchoring material that maybe used for any particular sensor is dependent upon one or more of thefollowing parameters: implantation site (e.g., location in the host),surface area, shape, size, geometry, mass, density, volume, surfacearea-to-volume, surface area-to-density, and surface area-to-mass. Forexample, a device with a greater mass as compared to a device with alesser mass may require more anchoring material to support the greatermass differential.

In preferred embodiments, the sensor of the described geometry isimplanted at the interface between two kinds of tissue, and ispreferably anchored to the more robust tissue type. For example, thesensor may be placed adjacent to an organ (for example, a kidney, theliver, or the peritoneal wall), or adjacent to the fascia below adiposetissue. When implanted in such a fashion, the sensor geometry minimizesforce transference, permitting non-anchored tissue to move over thesmooth surface of the sensor, thereby minimizing the force transferredto the underlying tissue to which the sensor is anchored. While it isgenerally preferred to anchor the sensor to the more robust tissue type,in certain embodiments it may be preferred to anchor the sensor to theless robust tissue type, permitting the more robust tissue to move overthe smooth surface of the sensor. While the sensor geometries ofpreferred embodiments are particularly preferred for use at tissueinterfaces, such sensors are also suitable for use when implanted into asingle type of tissue, for example, muscle tissue or adipose tissue. Insuch embodiments, however, the sensor geometry may not confer anybenefit, or only a minimal benefit, in terms of force transference.Other benefits may be observed, however. In another embodiment, thesensor may be suspended, with or without sutures, in a single tissuetype, or be placed between two tissue types, and anchoring materialcovering substantially the entire surface of the device may be employed.

In some alternative embodiments, a mechanical anchoring mechanism, suchas prongs, spines, barbs, wings, hooks, helical surface topography,gradually changing diameter, or the like, may be used instead of or incombination with anchoring material such as described herein. Forexample when an oblong or cylindrical type sensor is implanted withinthe subcutaneous tissue, it may tend to slip along the pocket that wasformed during implantation, particularly if some additional space existswithin the pocket. This slippage can lead to increased inflammatoryresponse and/or movement of the sensor prior to or during tissueingrowth. Accordingly, a mechanical mechanism can aid in immobilizingthe sensor in place, particularly prior to formation of a mature foreignbody capsule. One example of mechanical anchoring means is shown on FIG.13B, at 179; however, it should be noted that the placement andconfiguration of a mechanical anchoring mechanism is broad in scope asdescribed herein.

FIG. 13A illustrates the surface of the sensor 140 in mechanical contactwith the overlying tissue 172, as well as the underlying muscle fascia174, due to the ingrowth of the fibrous tissue and vasculature. In thisembodiment, any surface of the sensor 170 covered with anchoringmaterial 176 is typically ingrown with fibrous, vascularized tissue 178,which aids in anchoring the sensor and mitigating motion artifact. Itmay be noted however, that in some cases, forces applied laterally tothis tissue may be translated to the sensor, and likewise to the fasciaside of the sensor, causing potential disruption of the interface withthe fascia. Therefore, although the radial profile of the side of thesensor incorporating the sensor head assists in preventing forces in thedistal subcutaneous tissue from exerting forces on the sensor head side,which is attached to the muscle fascia by an anchoring material,complete coverage of the device with anchoring material may not bepreferred in certain embodiments.

An anchoring material covering the sensor may also make it difficult toremove the sensor for maintenance, repair, or permanent removal if itsfunction is no longer necessary. It is generally difficult to cut downthrough the surrounding tissue to the surface of the sensor without alsocutting into the anchoring material and leaving some of it behind in thepatient's tissues. Leaving a portion of the sensor free of anchoringmaterial enables the sensor to be more easily removed by locating thesmooth surface, grasping the sensor with a holding tool, and thencutting along the plane of the anchoring material to fully remove thesensor. In certain embodiments, however, it may be desirable for theentire surface of the sensor, or a substantial portion thereof, to becovered with an anchoring material. For example, when implanted into asingle tissue type (subcutaneous adipose tissue, or muscle tissue), itmay be desirable to have anchoring over all or substantially the entiresurface of the sensor. In still other embodiments, no anchoring at allmay be preferred, for example, in sensors having very small dimensions.One contiguous sheet of anchoring material can be employed, or two ormore different sheets may be employed, for example, an array of dots,stripes, mesh, or other suitable configuration of anchoring material.

FIG. 13B illustrates a preferred embodiment wherein the surface 180 ofthe sensor facing away from the muscle fascia 174 (e.g., surfaceopposite the sensing region) is not covered with anchoring material, butinstead is a smooth, biocompatible material that is non-adhesive totissues 182. It is also generally preferred that the surface 180 facingaway from the fascia have a radius of curvature, although in certainembodiments it may also be acceptable for the surface to have anothershape, for example, a flat surface. When mechanical force is applied tothe overlying tissue, the force is dissipated in the elastic foreignbody response overlying the sensor, and is not effectively translatedthrough the sensor to the biointerface with the fascia. This preferredconfiguration decreases damage to the biointerface caused by externalforces. Moreover, for sensor removal, the surgeon can easily find theoutermost surface of the sensor without cutting into it. The outermostaspect of the sensor is surrounded by a thick foreign body capsule,which substantially frees the sensor when it is cut free. Once thesensor is located and grasped by the surgeon, complete removal bycareful dissection of the face of the sensor associated with the fasciacan be readily accomplished. Transference of lateral force around asensor with anchoring material covering the entire surface compared tosensors with anchoring materials covering only the face with the sensorhead are depicted in FIG. 13A and FIG. 13B, respectively.

In other words, in FIG. 13A, vascular and fibrous tissues 178 intertwinewith the anchoring material 176. When a force is applied to tissueoverlying the sensor of FIG. 13A, it may be translated into the sensorbecause of the mechanical attachment of the sensor to the fibroustissue, which grows into the interstices of the anchoring material. Incontrast, the sensor of FIG. 13B is smooth on the side opposite thefascia. When mechanical energy is applied to the overlying tissue, it isnot effectively transferred to the sensor because the tissue is notattached to the sensor nor intertwined with it.

It may be noted that the smoothness of the surface of the device can bemeasured by any suitable method, for example, by profilometry asdescribed in U.S. Pat. No. 6,517,571, the contents of which is herebyincorporated by reference in its entirety. Measurements are preferablytaken from representative areas (for example, square areas of 500microns length on each side) of the smooth surface of the device. Asurface is generally considered “smooth” if it has a smoothness of lessthan 1.80 microns RMS. Surfaces with a smoothness greater than or equalto 1.80 microns RMS are generally considered “rough.” In certainembodiments, however, the cut-off between “rough” and “smooth” may behigher or lower than 1.80 microns RMS.

Profilometry measurements can be performed with a Tencor Profiler ModelP-10, measuring samples of square areas of 500-micron length per side.Surface data measurements can be made using the Tencor Profiler ModelP-10 with a MicroHead or Exchangeable Measurement Head (stylus tipradius of 2.0 microns with an angle of 60°). Preferred menu recipesettings for the profilometer are as follows: Scan length: 500 micronsScan speed: 50 microns/second Sampling rate: 200 Hz No. of traces: 50Spacing between traces: 10 microns No. of points/trace: 2000 Pointinterval: 0.25 microns Stylus force: 5 mg Range/resolution: 65microns/0.04 Angstroms Profile type: Peaks and valleys Waviness filter:45 mm/1.8 in.

Cursors can be set at each end of the length of each area to be sampled,for example, at 0 microns and at 500 microns. Scans can be performed inthe longitudinal direction of tubular samples, or in any convenientdirection for samples of other shapes. A parameter correlating toroughness of surfaces of the devices of preferred embodiments is Rq,which is the Root-Mean-Square (RMS) roughness, defined as the geometricaverage of the roughness profile from the mean line measured in thesampling length, expressed in units of microns RMS.

The use of an alternative (finer) waviness filter during profilometryallows for materials that include gross surface non-uniformities, suchas corrugated surfaces made from microscopically smooth materials.

In certain embodiments it is preferred that the smooth surfaces of thedevice are smooth in their entirety, namely, along the entire length ofthe surface. For surfaces of relatively uniform smoothness along theirentire length, surface measurements are preferably made at three pointsalong the length of the surface, specifically at points beginning at onefourth, one half and three fourths of the length of the surface asmeasured from one end of device to the other. For surfaces ofnon-uniform surface character along their entire length, five samplesequally spaced along the length are preferably considered. Themeasurements from these 3-5 sample areas are then averaged to obtain thesurface value for the smooth surface. In other embodiments, however,other methods of obtaining measurements may be employed.

An article entitled “Atomic force microscopy for characterization of thebiomaterial interface” describes the use of AFM for consideration ofsurface smoothness (Siedlecki and Marchant, Biomaterials 19 (1998), pp.441-454). AFM may be usefully employed for the smoothness evaluation ofdevice surfaces where the resolution of profilometry is marginallyadequate for extremely smooth surfaces. However, for purposes of thepreferred embodiments, profilometry measurements made using theabove-described Tencor profilometer are generally adequate fordetermining the smoothness of the device surface

EXAMPLES

Weekly infusion studies were conducted for four-weeks to investigate theeffects of sensor geometries of preferred embodiments on the functionalperformance of glucose sensors. A first group of sensors (n=5) includeda cylindrical geometry similar to that described with reference to FIG.4. A second group of sensors (n=6) included a thin, oblong geometrysimilar to that described with reference to FIG. 5. The functionalaspects of each sensor were constructed in a similar manner, such asdescribed in Published Patent Application No. 2003/0032874, which isincorporated herein by reference. The sensors were then implanted intothe subcutaneous tissue in dogs between the fascia and adipose tissues,and sensor function evaluated by weekly glucose infusion tests.

The implantation entailed making a 1 -inch incision, then forming apocket lateral to the incision by blunt dissection. After placement ofthe device with the sensing region facing towards the fascia, a suturewas placed by pulling the connective tissue together at the end of thedevice proximal to the incision. It is believed that the sutures heldeffectively during wound healing and device integration with tissues.

FIG. 14A is a graph showing the percentage of functional sensors fromthe two different sensor geometry groups. The x-axis represents time inweeks; the y-axis represents percentage of functional sensors for eachgroup during the weekly infusion studies. It is known that an initialstartup period exists for sensors implanted in the subcutaneous space,between about one and three weeks, during which delayed sensorfunctionality may be related to the amount and speed of tissue ingrowthinto the biointerface, as described with reference to copending U.S.patent application Ser. No. 10/647,065 filed Aug. 22, 2003 and entitled“POROUS MEMBRANE FOR USE WITH IMPLANTABLE DEVICES.” Interestingly, bothsensor geometries functioned substantially as expected in that themajority of devices were functional by week four. However, the sensorsof the thin, oblong sensor geometry group showed faster start-up timesas evidenced by a higher percentage of functional sensors at weeks twoand three.

The delayed start-up of the cylindrical group as compared to the thin,oblong group is believed to be due to delayed ingrowth of tissues orlack of ingrowth of tissues, which effects device function through lackof glucose sensitivity, compromised function after start-up, lowsensitivity, and long time lags. One cause for this delay of or lack oftissue ingrowth in the cylindrical group is believed to be the placementof the sensing region on the device. Particularly, when a sensor isimplanted in the subcutaneous space between two tissue types, such asthe adipose subcutaneous tissue and the fascia, optimal tissue ingrowthmay occur when the sensor is directly adjacent and fully engaged withthe fascia, such as described with reference in FIG. 5B. In contrast tothe sensors of the thin, oblong geometry group, when the sensors of thecylindrical are implanted in the pocket formed between the two tissuetypes, a space may exist adjacent at least a portion of the sensingregion between the two tissue types creating delayed or lack of tissueingrowth due to spacing from soft tissue. Accordingly, it may beadvantageous to design the sensing region on a sensor body such that theentire sensing region is directly adjacent to the fascia or similartissue immediately after implantation.

Some additional observations may be directly related to the delayedsensor function in the cylindrical sensors of this study. For example,the thin, oblong geometry as compared to the cylindrical geometry doesnot protrude from the host as much and is less amenable to accidentalbumping or movement, and less available for patient “fiddling.” Thus, itmay be inferred that overall dimensions may effect sensor geometry suchthat by increasing the discreetness of the geometry (e.g., mass, shape,dimensions), sensor functionality may improve. As another example, thethin, oblong geometry as compared to the cylindrical geometry is lesssusceptible to torsion and/or rotational forces, which may create motionartifact and therefore chronic inflammatory response at thedevice-tissue interface. In other words, with the sensor head orienteddown towards the fascia, and nearer to the center of the sensor,downward pressure on either end is not transferred as shear force to thesensor head; even if the sensor is moved, the sensor head more likelyremains adjacent to the tissue so that it may heal in a favorablefashion, unlike the sensors wherein the tip is positioned on an end ofthe sensor body, which can leave a space after lateral movement. Fromthis observation, it may be hypothesized that surface area-to-volumeratio may effect the function of the sensor. Particularly, an increasedsurface area-to-volume ratio, particularly as a consequence of reducingthe volume of the sensor, may decrease the effects of forces (e.g.,torsion, rotational, and shearing) caused by behavioral and environmentmovement. Similarly, optimization of surface area-to-mass and surfacearea-to-density ratios may impact healing.

FIG. 14B is a graph showing the average R-value of sensors from a studyof the two different sensor geometries implanted in a host. The x-axisrepresents time in weeks; the y-axis represents average R-value for eachgroup of sensors during each weekly infusion study. R-values wereobtained by correlating sensor output to the externally derived metervalues, and performing a least squares analysis, such as described withreference to copending U.S. patent application Ser. No. 10/633,367 filedon Aug. 1, 2003 and entitled “SYSTEM AND METHODS FOR PROCESSING ANALYTESENSOR DATA.”

It may be observed that both geometry groups performed with sufficientaccuracy by week three (e.g., greater than 0.79 R-value constitutessufficient accuracy in one example). It may also be observed that thesensors of the thin, oblong group increased in accuracy and were moreconsistent than the sensors of the cylindrical group. It is believedthat the slightly improved performance of the thin, oblong group ascompared to the cylindrical group may be due to a variety of factors,including those described with reference to FIG. 11A, and additionalfactors such as surface area, size, mass, density, volume, surfacearea-to-volume, surface area-to-density, and surface area-to-mass.

From the observations of the above described study, optimization of thesensor geometry may additionally include: 1) density optimization tobetter correspond to the density of tissue (e.g., fascia or adipose), 2)surface area-to-volume optimization by increasing the surfacearea-to-volume ratio of the sensor, 3) size optimization by decreasingthe overall size, mass, and/or volume of the sensor, and 4) surfacearea-to-mass optimization by increasing the surface area-to-mass ratioof the sensor, for example.

Table 1 illustrates additional analysis from the above describedinfusion study, including a comparison of average R-value at week 4 andstandard deviation at week 4 for the two groups of sensors. TABLE 1Thin, oblong Cylindrical geometry with Results of Geometry Geometry withsensor on curved Study sensor on curved end major surface AverageR-value at 0.73 0.87 Week 4 Standard Deviation 0.41 0.08 at Week 4

As described above with reference to FIG. 11B, the average R-value atweek 4 was better for the thin, oblong group as compared to thecylindrical group. Additionally the average standard deviation of thethin, oblong group as compared to the cylindrical group was much lower,indicating greater consistency and tighter tolerances with the thin,oblong group. As described above with reference to FIGS. 11A and 11B,this performance differential may be due to additional geometric factorssuch as surface area-to-volume ratio, size, mass, and surfacearea-to-density ratio, for example.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention as embodied in the attached claims.All patents, applications, and other references cited herein are herebyincorporated by reference in their entirety.

1. An implantable sensor for use in measuring a concentration of ananalyte in a bodily fluid, the sensor comprising: a body comprising asensing region adapted for transport of analytes between the sensor andthe bodily fluid, wherein the sensing region is located on a curvedportion of the body such that when a foreign body capsule forms aroundthe sensor, a contractile force is exerted by the foreign body capsuletoward the sensing region, wherein the body comprises a first surfaceand a second surface, wherein the sensor region is situatedapproximately at a center point of said first surface, and wherein thesensor is a subcutaneous sensor suitable for implantation in a softtissue of a body.
 2. The sensor of claim 1, wherein the sensor comprisesa plurality of sensor regions.
 3. The sensor of claim 1, wherein saidsecond surface is flat.
 4. The sensor of claim 1, wherein said secondsurface comprises a curvature.
 5. The sensor of claim 1, wherein saidfirst surface, when viewed from a direction perpendicular to a center ofsaid first surface, has a substantially oval profile.
 6. The sensor ofclaim 1, wherein said first surface, when viewed from a directionperpendicular to a center of said first surface, has a substantiallycircular profile.
 7. The sensor of claim 1, wherein the body issubstantially cylindrical defined by a curved lateral surface and twoends.
 8. The sensor of claim 1, wherein the body is substantiallycylindrical defined by a curved lateral surface and two ends, andwherein at least one of said ends comprises the substantially curvedportion on which the sensor region is located.
 9. The sensor of claim 1,wherein the second surface comprises anchoring material thereon forsupporting tissue ingrowth.
 10. The sensor of claim 1, furthercomprising a mechanical anchoring mechanism formed on the body.
 11. Thesensor of claim 1, wherein said curved portion comprises a plurality ofradii of curvature.
 12. The sensor of claim 1, wherein said curvedportion comprises a radius of curvature between about 0.5 mm and about10 cm.
 13. The sensor of claim 1, wherein the body comprises a firstsurface on which said sensing region is located and a second surface,and wherein the first and second surfaces together account for at leastabout 40% of the surface area of the device.
 14. The sensor of claim 1,and wherein edges of the first surface are rounded and transitionsmoothly away from the first surface.
 15. The sensor of claim 1, whereinthe body defines a surface area, and wherein between 10% and 100% of thesurface area is convexly curved.
 16. The sensor of claim 1, wherein thebody comprises plastic.
 17. The sensor of claim 16, wherein the plasticis selected from the group consisting of thermoplastic and thermoset.18. The sensor of claim 17, wherein the thermoset is selected from thegroup consisting of epoxy, silicone, and polyurethane.
 19. The sensor ofclaim 1, wherein the body comprises a material selected from the groupconsisting of metal, ceramic, and glass.
 20. The sensor of claim 1,further comprising a porous biointerface material that covers at least aportion of the sensing region.
 21. The sensor of claim 20, wherein thebiointerface material comprises interconnected cavities dimensioned andarranged to interfere with formation of occlusive cells.
 22. The sensorof claim 1, wherein the sensor is a glucose sensor.
 23. A whollyimplantable sensor adapted to measure a concentration of an analyte in abodily fluid, comprising: a wholly implantable body comprising a sensingregion adapted for transport of analytes between the sensor and thebodily fluid, wherein the sensing region is located on a curved portionof a first surface of said body, wherein the body further comprises asecond surface, wherein the sensing region is situated approximately ata center point of said first surface, wherein the sensor is asubcutaneous sensor suitable for implantation in a soft tissue of abody, and wherein said first surface comprises a porous material thereonfor supporting tissue ingrowth.
 24. An implantable sensor adapted tomeasure a concentration of an analyte in a bodily fluid, comprising: abody having a first surface and, opposite thereto, a second surface,wherein the first surface is generally planar, slightly convex, and hasrounded edges, with a sensor region located on the first surface that isspaced away-from the rounded edges and approximately at a center pointof said first surface, wherein the first surface is sufficiently convexthat when a foreign body capsule forms around the sensor, contractileforces are exerted thereby generally uniformly towards the sensingregion, and wherein the sensor is a subcutaneous sensor suitable forimplantation in a soft tissue of a body.